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Response-Independent Survival Benefit in Metastatic Colorectal Cancer: A Comparative Analysis of N9741 and AVF2107

Axel Grothey, Eric E. Hedrick, Robert D. Mass, Somnath Sarkar, Sam Suzuki, Ramesh K. Ramanathan, Herbert I. Hurwitz, Richard M. Goldberg, Daniel J. Sargent

From the Mayo Clinic, Rochester, MN; Genentech Inc, South San Francisco, CA; Translational Genomics Research Institute, Scottsdale, AZ; Duke University, Durham, NC; and University of North Carolina, Chapel Hill, NC

Corresponding author: Axel Grothey, MD, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905; e-mail: grothey.axel{at}mayo.edu

Purpose: In the phase III study AVF2107g, bevacizumab (BV) demonstrated a survival benefit when added to irinotecan, fluorouracil, and leucovorin (IFL) in first-line metastatic colorectal cancer (mCRC). In a parallel phase III study, Intergroup N9741, oxaliplatin plus fluorouracil and leucovorin (FOLFOX) also demonstrated a survival benefit compared with IFL. As these two superior therapies have differing mechanisms of action, we explored whether the improved survival associated with the superior therapy was dependent on tumor response.

Patients and Methods: For these retrospective, exploratory analyses, patients were defined as responders or nonresponders by whether complete or partial response was achieved with first-line therapy.

Results: Compared with IFL alone, BV plus IFL and FOLFOX each demonstrated statistically significant improvements in progression-free survival (PFS) and overall survival (OS) regardless of objective tumor response. BV-treated nonresponders had a hazard ratio (HR) of 0.63 (P = .0001) for PFS and 0.76 (P = .0188) for OS compared with IFL-treated nonresponders. FOLFOX-treated nonresponders had an HR of 0.75 (P = .0029) for PFS and 0.74 (P = .0030) for OS compared with IFL-treated nonresponders.

Conclusion: In both AVF2107g and N9741, objective response did not predict the magnitude of PFS or OS benefit from the superior therapy; nonresponders, despite a poorer prognosis than responders, achieved extended PFS and OS from BV plus IFL or FOLFOX compared with IFL. On the basis of these data, tumor response in metastatic colorectal cancer is not a necessary factor for a therapy to provide benefit to an individual patient.

Supported by National Cancer Institute Grant No. CA25224, by Sanofi Synthelabo (now Sanofi-Aventis), and by Pharmacia (now Pfizer).

Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL, and at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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